阿茲海默氏症 (Alzheimer’s disease) 是一種常見的神經退化性疾病，其特徵為大腦中神經細胞漸進性的損傷以及微膠質細胞的過度活化。除此之外，β-澱粉樣蛋白 (Aβ) 的堆積是阿茲海默氏症中重要的病理特徵，並在疾病的發展中扮演重要的角色。由於β-澱粉樣蛋白的製造與清除失衡，使得β-澱粉樣蛋白產生堆積。而過多的β-澱粉樣蛋白會過度活化微膠質細胞，也會引發神經細胞之粒線體功能缺陷。病理過程造成慢性神經性發言及神經性退化的後果，最終導致神經元死亡。然而，β-澱粉樣蛋白對於微膠質細胞之粒線體的影響以及相關機制，卻較少被探討。因此，我們假設β-澱粉樣蛋白會引起微膠質細胞中粒線體功能的損傷，並間接影響微膠質細胞所調控的免疫發炎反應。本研究將微膠質細胞暴露在β-澱粉樣蛋白下，並檢測其粒線體的功能，包含生物能量（bioenergetics）、粒線體形態，以及相關訊號傳遞路徑的變化。此外，一個新型硫脲小分子藥物＃326，由於具有抗發炎能力，因此本篇研究進一步測試＃326是否能透過抗發炎的反應，來挽救受到β-澱粉樣蛋白所導致的粒線體功能缺失。本篇研究結果顯示，β-澱粉樣蛋白會降低粒線體的生物能量及改變粒線體形態與分佈，造成微膠質細胞中粒線體的功能損害。此外，β-澱粉樣蛋白會促進微膠質細胞中ERK的磷酸化。然而，在β-澱粉樣蛋白的作用下，#326不僅能挽救粒線體的功能缺失，並能降低β-澱粉樣蛋白引發之ERK過度磷酸化。據此推斷，#326可能透過調解ERK的訊號傳遞路徑，改善β-澱粉樣蛋白引起的線粒體失能。總結以上，我們的研究結果顯示#326能改善β-澱粉樣蛋白對微膠質細胞中線粒體功能的損害，而這種粒線體保護功能，可能與其調解ERK1/2的過度磷酸化作用有關。此外，透過研究新型的硫脲小分子藥物#326的作用機制，或許能得到阿茲海默氏症病理研究的相關線索，甚至對神經退化性疾病的藥物治療發展中有所幫助。Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the progressive neuronal loss and overactive microglia. Besides, amyloid-β (Aβ) is a histopathological hallmark in AD, which plays a crucial role in the pathogenesis of this disease. The imbalance between Aβ production and clearance leads to the accumulation of Aβ in extracellular and intracellular compartments. Growing evidence suggests that excessive amyloid-β (Aβ) accumulation instigates early deficits in mitochondrial function and causes a self-propelling degeneration cycle which sustains chronic neuroinflammation induced by microglial and eventually lead to neuronal damages. Nevertheless, how Aβ affects mitochondrial function in microglia is still elusive. In this study, it was hypothesized that Aβ would cause mitochondrial defects in microglia and further exacerbate microglial activation which is the causation of neuronal inflammation in AD.To investigate this premise, mitochondrial function, including mitochondrial bioenergetics, mitochondrial morphology, and mitochondrial relative pathway were tested in microglial cells challenged with Aβ. In addition, the protective effects of a novel thiourea, compound #326, which possesses anti-inflammatory effect were also been examined in this study. Our data indicated that Aβ impaired mitochondrial function as evidenced by the decreased bioenergetics, fragmented mitochondria, and abnormal distribution. In addition, our results also showed the activation of extracellular-signal regulated kinase (ERK) phosphorylation under Aβ stimulation. Intriguingly, our data indicated that the rescuing effects of the novel compound on the aberrant bioenergetics elicited by Aβ are involved in the modulation of ERK activity that is highly associated with mitochondrial damages under the circumstances of Aβ toxicity. Therefore, studying the mechanism of the new thiourea, compound #326, may provide the clues to study the pathology of AD, and even improve the design of pharmacological intervention for AD.